DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Applicant' s amendment filed 05/05/2026 is acknowledged. Claims 74-75, 80, 85-87, and 91 have been amended. Claims 83-84 have been cancelled. Claims 74-76, 78-80, 85-87, 91-92, and 95 are pending in the instant application and the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The 112(b) rejection of claim 87 is withdrawn in view of the amendments to the claims.
The 101 rejections are maintained and modified/clarified in view of the amendments.
The prior art rejection(s) under 35 USC 102 directed to claim(s) 74-76, 78-80, 83, 91-92 and 95 as being anticipated by Abkevich is withdrawn in view of the amendments by the claims.
The prior art rejection(s) under 35 USC 103 directed to claims 74-76, 78-80, 85-87, 91-92, and 95 over Abkevich are maintained and modified in view of the amendments.
The non-statutory double patenting rejections are modified as necessitated by claim amendments. As noted in the previous rejection in the “Status of the Prior Rejections/Objections” section, these were made over reference Abkevich (WO 2016/025958 A1). The headers have now been corrected to reflect this previously identified clerical error.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
Claim 92 is objected to because of the following informalities:
Claim 92: The terms “3laparib3in” and “3laparib” appear to be OCR errors or similar of “oxalaplatin” and “olaparib”, respectively, from the claim set dated 01/15/2026.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
Claims 74-76, 78-80, 85-87, 91-92, and 95 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) abstract ideas and natural phenomenon. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, each claim is directed to a process.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
The claims are directed to a method of detecting homologous recombination (HR) deficiency status of a BRCA deficient, TNBC cell of a patient comprising sequencing DNA from a sample comprising the cell of the patient, comprising: sequencing DNA isolated from a sample, wherein the sequencing results comprise a combined number of LOH regions, TAI regions, and LST regions in at least 10 pairs of human autosomes of greater than equal to 33, and wherein the TNBC cell of the patient is thereby HR deficient.
The claim remains directed to the natural phenomenon of the correlation between the number/status of the LOH regions, TAI regions, and LST regions and the homologous recombination deficiency status of the sampled cell(s), as observed by the sequencing.
Further, by reciting the combined number of regions required to determine the HR deficiency status of a the BRCA deficient TNBC cell of the patient, the claims inherently recite a calculation for combining the number of regions (e.g., addition). Thus, the claims still recite the abstract idea of a mathematical calculation, including one that may be performed in the human mind.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 74, the claim recites sequencing DNA isolated from a sample comprising the TNBC cell of the patient. Such sequencing represents insignificant extra-solution activity required to acquire the status of the regions and the HR status of the TNBC cell(s) of the patient. See MPEP 2106.04 regarding insignificant extra-solution activity.
Regarding claims 75-76 and 78-80, the claims recite lengths/characteristics of regions. As such, they represent thresholds for the judicial exception(s) (i.e., features correlated in the natural phenomenon and/or features of the algorithm in the mathematical calculation) , i.e., the data to be manipulated in the judicial exception(s) [insignificant extra-solution activity], and thus fail to integrate them into practical applications.
Regarding claims 85-87, the claims recite characteristics of the chromosomes and/or numbers of genomic loci sequenced/analyzed.
As above, the choice of particular data to be manipulated in the judicial exception amounts to extra-solution activity. See MPEP 2106.04(d). Likewise, the choice of the chromosomes in the abstract idea steps of detecting amounts to the same.
Regarding claims 91-92, the claims recite identifying the patient as likely to respond to a cancer treatment based on identifying the cancer cell as likely HRD. The claims fail to recite actual treatment steps, further encompassing mental processes, and thus do not integrate the claims into a practical limitation. See also MPEP 2106.04(d)(2): “If the limitation does not actually provide a treatment or prophylaxis…then it cannot integrate a judicial exception under the ‘treatment or prophylaxis’ consideration.”
Regarding claims 95, the claim recites that the combined number consists of the three types of regions. Thus, the limitation remains directed to the calculation/correlation and thus fails to integrate the claim into a practical limitation.
Step 2B. Does the claim amount to significantly more?
Each of the limitations discussed in Step 2A encompasses an abstract idea and/or is directed to the natural phenomenon, the selection of a particular type of data to use with the judicial exception(s), or a generically recited sequencing limitations that are well-known and routine utilized to furnish data for the judicial exception(s) (i.e., insignificant extra-solution activity).
In particular, MPEP 2105.06(d)(II) vii. Amplifying and sequencing nucleic acid sequences recites that such sequencing is well-known and conventional. Additionally, Karakoc (Karakoc E, et al. Detection of structural variants and indels within exome data. Nat Methods. 2011 Dec 18;9(2):176-8) recites that whole exon sequencing is widespread and relevant to structural variant detection (para 1), wherein Marian (Marian AJ. Sequencing your genome: what does it mean? Methodist Debakey Cardiovasc J. 2014 Jan-Mar;10(1):3-6.) teaches that each exome comprises approximately 13,500 polymorphic loci (Abstract). It is noted that instant para [0094] also states whole exome sequencing may be used.
Samorodnitsky (Samorodnitsky E, et al. Comparison of custom capture for targeted next-generation DNA sequencing. J Mol Diagn. 2015 Jan;17(1):64-75.) teaches commercial targeted panels for SNV and copy number detection via sequencing (entire document, e.g., abstract and title) and that clinical laboratories use custom gene capture panels (para 1).
For this reason, sequencing a particular number of polymorphic loci on a particular set or subset of chromosomes is determined to be well-understood, routine and conventional, and thus fails contribute significantly more. Such likewise amounts to selecting the data to be manipulated in the judicial exception(s), as discussed above and in MPEP 2106.05(g).
Further, the courts have found that analyzing DNA to provide sequence information or detect allelic variants (Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546) is well-understood, routine, and conventional activity. See also MPEP 2106.05(d).
As stated in MPEP2105.05(I), an inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). Even if the elements of the abstract ideas or the choice of the sample were found novel, the courts have been clear that such is insufficient to amount to significantly more. See, also, Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015) regarding a novel sample being insufficient to furnish “significantly more”.
Claim Rejections - 35 USC § 103
Claim(s) 74-76, 78-80, 85-87, 91-92, and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abkevich (WO 2016/025958 A1; published 02/18/2016).
Regarding claims 74 and 95, Abkevich teaches a method of determining an HRD status in a sample from a BRCA deficient, TNBC patient (entire document, e.g., para [0153]; Fig. 16; para [00349]: “line at 42 represents the HRD threshold between low [HRD] and high”; see para [00344-345]: “TNBC cohort…Fig. 15…distribution of HRD scores in the cohort”; para [00349]: “the distribution of HRD scores … as defined by BRCA mutation status [in the cohort]”; emphasis added), comprising:
sequencing DNA isolated from a sample comprising the TNBC cell of the patient (para [00293]: “sequencing on Illumina HiSeq2500”; para [00339]: “a capture panel which targets ~54,000 SNPs”…Allele counts from the sequencing…this panel”)
detecting a combined number of LOH, TAI, and LST regions in at least one pair of human chromosomes (para [00344-355]: “HRD scores”; para [00342]: “The combined score (HRD score) was the summation of the LOH/TAI/LST scores”; instant claim 95; across the genome: para [00293]; [00153])
detecting deficiency when the number of LOH, TAI, and LAST regions is greater than 33 (para [00345]: “scores > 42 were considered to have high HRD…The bimodality illustrated in Figure 15 indicates that HRD scores effectively distinguished HR deficient and non-deficient states in the tumor”; see also Fig. 15 and Table 6, wherein this analysis inherently included BRCA deficient samples; also, para [00349]: “by BRCA mutation status…dotted line at 42 represents the HRD threshold”)
Abkevich applies the method to a cell of a sample (entire document, e.g., para [0045] and para [00153]).
Additionally, while there is a single method of identifying the regions utilized in the cited example methods and it would be reasonable to conclude that the same methods of targeted sequencing were utilized with the TNBC cohort as with the previous cohorts, the TNBC cohort does not explicitly teach that the regions were identified in sequencing.
Abkevich teaches sequencing in the citations above and a variety of substitutable methods in para [0086].
Regarding claims 75-76, in the method of Abkevich, Abkevich teaches that the number of LOH regions >15 Mb in length but shorter than the length of the respective complete chromosome was used in calculating the HRD score (para [00342]).
Regarding claims 78-79, in the method of Abkevich Abkevich teaches that number of TAI regions >11 Mb in length with allelic imbalance that extend to one of the subtelomeres, but do not cross the centromere was used in calculating the HRD score (para [00342]).
Regarding claim 80, in the method of Abkevich Abkevich teaches that number of LST regions was the number of breakpoints between regions longer than 10 Mb (para [00342]). Abkevich teaches that the LSTs identified are somatic changes (para [0046] and [0048]: “LST refers to any somatic copy number…breakpoint”).
Regarding claim 83, in the method of Abkevich, by teaching that the method is performed using a panel that targets SNPs across the complete genome (para [00293]), Abkevich teaches that at least one pair of the human chromosomes are autosomes, given that only one pair of human chromosomes are sex chromosomes (see para [0002] or [0014]).
Regarding claims 85-87, in the method of Abkevich, Abkevich teaches that the number of Indicator LOH Regions, Indicator TAI Regions and Indicator LST Regions are determined in at least 21 pairs of human chromosomes (para [00202]; see also the rejections of claims 75, 78, and 80).
Abkevich teaches assaying 50,000 selected SNPs across the complete genome (para [00293]; instant claim 87; see also para [00285] and [0092-93]).
Regarding claims 91-92, in the method of Abkevich Abkevich teaches predicting response of a patient to DNA damaging agent (see instant claim 92) cisplatin based on HR Deficiency status (para [00352]; Table 18; see also [00153] and para [00160]).
In the embodiment of determining HRD status in a BRCA deficient TNBC cell of a patient, Abkevich fails to explicitly teach:
considering the combined number of LOH/TAI/LST regions in autosomes alone (instant claim 74); and
considering a specific amount of loci per autosomal pair (instant claim 86).
Abkevich teaches excluding certain chromosomes from the analysis of HRD, such as the sex chromosomes if assessing males (para [0098]). Abkevich further teaches that it can be helpful to exclude chromosomes with unusually high levels of chromosomal aberrations in certain cancers when analyzing samples (para [0098]), and that separate cutoffs may be relevant to ploidy in BRCA intact and deficient samples (para [0049]; instant claim 74).
Abkevich teaches determining at least 150 polymorphic genomic loci in at least 22 autosome pairs in an embodiment that allows predicting a response to a cancer treatment based on Indicator LOH Regions, Indicator TAI Regions, and Indicator LST Regions (para [00285]; instant claim 86).
First, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the data acquisition method in the method of detecting HR deficiency status of a BRCA deficient, TNBC cell of a patient, if for the sake of argument it were not sequencing, for sequencing, as such was an art recognized equivalents for the same purpose, as taught by Abkevich. See MPEP 2144.06(II).
Second, while an anticipating threshold is taught by Abkevich (see MPEP 2131.03: prior art which teaches a range which is within a claimed range anticipates the range; i.e., >33 includes the range >42), the threshold for the combined number of chromosomal aberrations is also matter of routine optimization. See MPEP 2144.05 and, for example, the teaching by Abkevich regarding utilizing different cutoffs for the LST component for BRCA1/2 intact and deficient samples based on ploidy (para [0049] and para [00298]).
Such is not found to be a critical feature of the instant invention at least because the instant specification defines BRCA deficient cells as inherently HR deficient (para [0093]: “deficient status for a pathway (e.g., HDR pathway) means at least one gene in the pathway … is deficient”, where in BRCA1 and BRCA2 are listed as HDR Pathway genes in Table 1 and HDR and HRD are defined as synonymous in para [0003]).
Further, instant para [0072-73] (and, it is also noted, Abkevich para [0064-65]) teach a large range of suitable combined scores above which a sample is characterized as having an HRD signature between 5 and 50, where >5 is identified as preferable and >42 most preferable. As such, the particular threshold chosen has not been identified to be critical to the invention.
Third, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to utilize only autosomes in the method of Abkevich, motivated by the desire to utilize the method in males with breast cancer (as genetic males lack pairs of sex chromosomes) and/or if it were identified that X chromosomes contained unusually high levels of chromosomal aberrations in the cancer of interest (i.e., BRCA deficient TNBC), as taught by Abkevich. See also omitting elements when the functions are not desired in MPEP 2144.04(II)(A).
Fourth, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have distributed the SNPs across the autosomal pairs such that there would have been 150 polymorphic loci per pair as such a number of sites and effective density across the chromosomes is a matter of routine optimization (instant claim 86). See MPEP 2144.05. Abkevich teaches optimization of SNP locations and supplemental sequencing at para [0092-93]).
There would have been a strong expectation of success as sequencing was a known equivalents to alternative methods for acquiring the status of LOH/TAI/LST regions according to Abkevich, which teaches acquiring the relevant data, and each amounts to the application of a known technique of a known method, e.g., the artisan would be able to exclude a given chromosome from either the panel or the data analysis.
Double Patenting
Claims 74-76, 78-80, 85-87, 91-92, and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. US 10,400,287 B2 in view of Abkevich (WO 2016/025958 A1; published 02/18/2016) and Telli (Telli ML, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3764-73. Epub 2016 Mar 8; as cited in the IDS dated 12/06/2022).
Both sets of claims are directed to detecting, in a sample comprising a cancer cell, a test value equal to or derived from the sum of the number of LOH Regions, the number of TAI Regions, and the number of LST breakpoint Regions, and utilizing a reference value via sequenced DNA molecules.
‘287 further teaches the definition of Indicator LOH regions of instant claim 75, of TAI Regions of 78, and, in part, the definition of LST Regions of 80 (but fails to explicitly teach that the flanking regions are >10 Mb); determining in 15 pairs of chromosomes (but not explicitly autosomes); a density of SNPS (but fails to explicitly teach 5000 loci or a number in each autosomal pair). ‘287 teaches administering a treatment regime including the treatments of claims 91-92, but does not explicitly identify the patient as likely to respond.
‘287 teaches that the cancer cell harbors a deleterious mutation in BRCA1 or BRCA2. “BRCA1/2” (claim 1) of instant claim 74 may be interpreted as “BRCA1 or BRCA2”.
‘287 fails to teach applying the method to a TNBC cancer cell of a patient.
Any additional limitations of the claims of ‘287 are encompassed by the open claim language “comprising” found in the instant claims.
Abkevich rectifies the above deficiencies by teaching the number of loci both overall and per autosomal pair; utilizing the combined number to identify patients likely to respond; each of the instant claimed thresholds; and that the method may be applied to a BRCA deficient TNBC sample/patient, as has been cited in at least the 103 rejection above.
Abkevich further teaches that the HRD-combined score captured significant BRCA1/2 deficiency information not captured by clinical variables (para [00335]) and a threshold of >42 in the HRD-combined score was an effective predictor of pathologic complete response [to treatment] such that 0% of non-deficient patients had pCR whereas 28% of those with HRD status [using the threshold] obtained pCR (para [00347]; Table 13), as cited and discussed in the 103 above.
The motivating reference Telli further teaches that TNBC are not amendable to certain targets that may work for other subtypes (pg. 3764, Introduction, para 1). Telli teaches that sporadic TNBC may bear substantial similarities to BRCA1/2-mutated cancers, including DNA repair defects that might predispose to platinum sensitivity, and clinical trials have identified improvement in pathological response with the addition of platinum, but at the cost of increased toxicity (pg. 3764, Introduction, para 1). Telli further teaches that a predictive biomarker for platinum sensitivity would be helpful to personalize the use of platinum agents, restricting their use to those who would benefit while avoiding unnecessary toxicity for those who would not (pg. 3764, Introduction, para 1).
Telli teaches that some mutations in BRCA are deleterious (pg. 3765, Training set used to establish HRD score threshold), wherein the artisan would recognize that some mutations may not be deleterious.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine the method ‘287 with method of Abkevich add at least the step of identifying the cancer cell as being HRD deficient by comparing to a threshold, motivated by the desire to utilize an effective predictor of treatment response that may provide more information than clinical variables alone, as taught by Abkevich. It further would have been obvious, in light of Abkevich’s application to TNBC and the teaching of Telli, to utilize the method for BRCA mutated/deficient TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli, wherein the HRD status would enable differentiation between mutations likely to be truly deleterious and those that may have unknown significance, as suggested by Telli. There would have been a strong expectation of success as both are directed toward assaying the same regions and represent the application of a known technique to a known method.
The all numeric limitations identified above in the 103 rejection are noted as matters of routine optimization for the same reasons. Any additional numeric difference between the instant claims and those of ‘287 is likewise identified as a matter of similar/overlapping ranges and routine optimization according to the same rationales.
Any additional limitations of the patented claims are encompassed by the open claim language “comprising” found in the instant claims.
Claims 74-76, 78-80, 85-87, 91-92, and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. US 12,421,555 B2 in view of Abkevich (WO 2016/025958 A1; published 02/18/2016) and Telli (Telli ML, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3764-73. Epub 2016 Mar 8; as cited in the IDS dated 12/06/2022).
Both sets of claims are directed to determining, in a sample comprising a cancer cell, the number of LOH Regions, the number of TAI Regions, and the number of LST breakpoint Regions, in BRCA deficient cancers (claim 9) or breast cancers (3).
‘555 teaches the lengths for LST regions, TAI, and LST region lengths (claim 4); that the chromosomes are not sex chromosomes [i.e., are autosomes] (claims 1 and 6); and a density of SNP loci that requires above 150 loci for the smallest human autosome (claims 1 and 6).
‘555 fails to explicitly recite that the breast cancer cell may be TNBC; using the number of regions to establish an “HRD status” based on a particular threshold; at least 20 human chromosomes and 5000 loci each; and that the contacting is part of a sequencing.
Abkevich rectifies the above deficiencies by teaching that the patient may have BRCA deficient TNBC; the number of loci both overall and per autosomal pair; and utilizing the combined number consisting of the regions to identify patients likely to respond with a threshold of 42 or greater; and targeted sequencing, as has been cited in at least the 103 rejection above.
Abkevich further teaches that the HRD-combined score captured significant BRCA1/2 deficiency information not captured by clinical variables (para [00335]) and a threshold of >42 in the HRD-combined score was an effective predictor of pathologic complete response [to treatment] such that 0% of non-deficient patients had pCR whereas 28% of those with HRD status [using the threshold] obtained pCR (para [00347]; Table 13). Abkevich teaches capture probes are part of targeted sequencing (e.g., para [0091-92]; [00148]; [00304]; [00315]); that such target enrichment enables targeted sequencing decreases sequencing costs and reduces genomic complexity (para [00339]); and that such is a known alternative to microarray [another probe technology] for the analysis of such data (para [0091]).
The motivating reference Telli further teaches that TNBC are not amendable to certain targets that may work for other subtypes (pg. 3764, Introduction, para 1). Telli teaches that sporadic TNBC may bear substantial similarities to BRCA1/2-mutated cancers, including DNA repair defects that might predispose to platinum sensitivity, and clinical trials have identified improvement in pathological response with the addition of platinum, but at the cost of increased toxicity (pg. 3764, Introduction, para 1). Telli further teaches that a predictive biomarker for platinum sensitivity would be helpful to personalize the use of platinum agents, restricting their use to those who would benefit while avoiding unnecessary toxicity for those who would not (pg. 3764, Introduction, para 1).
Telli teaches that some mutations in BRCA are deleterious (pg. 3765, Training set used to establish HRD score threshold), wherein the artisan would recognize that some mutations may not be deleterious. Telli teaches that HRD status provides an improvement over clinical variables or BRCA1/2 mutation status (pg. 3772, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to combine the method ‘555 with method of Abkevich add at least the step of identifying the cancer cell as being HRD deficient by comparing to a threshold consisting of the combined number of regions, motivated by the desire to utilize an effective predictor of further treatment response that may provide more information than clinical variables alone, as taught by Abkevich. It further would have been obvious, in light of Abkevich’s application to BRCA deficient TNBC and the teachings of Telli, to utilize the method for BRCA mutated/deficient TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli, wherein the HRD status would enable differentiation between mutations likely to be truly deleterious and those that may have unknown significance, as suggested by Telli. It further would have been obvious to utilize sequencing, motivated by the desire to reduce genomic complexity, as taught by Abkevich; such is a known species of the genus of probe-based assays and as such represents the application of a known alternative. There would be a strong expectation of success as both are directed toward assaying the same regions and represent the application of a known technique to a known method.
The all numeric limitations identified above in the 103 rejection are noted as matters of routine optimization for the same reasons. Any additional numeric difference between the instant claims and those of ‘555 is likewise identified as a matter of similar/overlapping ranges and routine optimization according to the same rationales.
Any additional limitations of the patented claims are encompassed by the open claim language “comprising” found in the instant claims.
The following claims are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable the indicated claims of the listed copending Applications in view of Abkevich (WO 2016/025958 A1; published 02/18/2016) and Telli (Telli ML, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3764-73. Epub 2016 Mar 8; as cited in the IDS dated 12/06/2022). These are provisional nonstatutory double patenting rejections.
Application No:
Instant claims rejected:
Rejected over claims:
Fails to recite:
Other notes:
17/353279
74-76, 78-92, and 94-95
59 and 61-67
• The cancer cell may be BRCA deficient TNBC; • ID’ing HRD status based on a test value and threshold; • Particular reference values/thresholds; • LST Region 10 Mb; • # of loci per autosome pair/loci overall; • # number of autosomes; • ID’ing a patient as a likely responder to particular therapies
• Broadly interpreted, ovarian, lung, etc. patients may comprise those whose TNBC, for example, has metastasized to the indicated sites
19/048611
74-76, 78-92, and 94-95
37-56
• The cancer cell may be TNBC (teaches breast cancer and BRCA deficiency); • ID’ing HRD status based on a test value and threshold; • Particular reference values/thresholds; • LST Region 10 Mb flanking regions; • # of loci per autosome pair; • # number of autosomes; • ID’ing a patient as a likely responder to particular therapies (claim 54 recites patient is candidate for platinum agents)
19/088496
74-76, 78-92, and 94-95
37-64
• The breast cancer cell may be TNBC and BRCA deficient; • ID’ing HRD status based on a test value and threshold; • Particular reference values/thresholds; • LST Region 10 Mb flanking regions; • # of loci per autosome pair; • # number of autosomes; • ID’ing a patient as a likely responder to particular therapies (claim 37 recites patient is candidate for chemotherapy; claim 39-40 recite instant claimed therapies)
All sets of claims are directed to a method of determining a number of LOH, TAI, and LST regions in a cancer cell of a patient, wherein the chromosomal aberrations are or may be of a minimum size and may be of a breast cancer where indicated above, and comprise methods where the regions are ascertained by sequencing.
Each of the co-pending applications fails to teach that the determined number of each may be utilized to identify an HRD status by combining the number of regions and comparing to a threshold, and fail to explicitly teach each of the other identified items in the table above.
Abkevich rectifies the above deficiencies by teaching the (Indicator) LST Region definition (including flanking region length); the number of loci both overall and per autosomal pair; utilizing the combined number to identify patients likely to respond; each of the instant claimed thresholds; that the test value may be derived from an arithmetic mean; identifying a patient as a responder to at least cisplatin; and that the method may be applied to a TNBC BRCA deficient sample/patient, as has been cited in at least the 103 rejection above.
Abkevich further teaches that that a sample has an "HRD signature" if such sample has a number of Indicator CA Regions exceeding a reference as described herein (para [0052]). Abkevich teaches that the HRD-combined score captured significant BRCA1/2 deficiency information not captured by clinical variables (para [00335]) and a threshold of >42 in the HRD-combined score was an effective predictor of pathologic complete response [to treatment] such that 0% of non-deficient patients had pCR whereas 28% of those with HRD status [using the threshold] obtained pCR (para [00347]; Table 13).
The motivating reference Telli further teaches that TNBC are not amendable to certain targets that may work for other subtypes (pg. 3764, Introduction, para 1). Telli teaches that sporadic TNBC may bear substantial similarities to BRCA1/2-mutated cancers, including DNA repair defects that might predispose to platinum sensitivity, and clinical trials have identified improvement in pathological response with the addition of platinum, but at the cost of increased toxicity (pg. 3764, Introduction, para 1). Telli further teaches that a predictive biomarker for platinum sensitivity would be helpful to personalize the use of platinum agents, restricting their use to those who would benefit while avoiding unnecessary toxicity for those who would not (pg. 3764, Introduction, para 1).
Telli teaches that some mutations in BRCA are deleterious (pg. 3765, Training set used to establish HRD score threshold), wherein the artisan would recognize that some mutations may not be deleterious. Telli teaches that HRD status provides an improvement over clinical variables or BRCA1/2 mutation status (pg. 3772, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to combine the method of the claims of any of the listed co-pending applications with method of Abkevich to add at least the step of identifying the cancer cell as being HRD deficient by comparing to a threshold, motivated by the desire to utilize an effective predictor of treatment response that may provide more information than clinical variables alone, as taught by Abkevich. It further would have been obvious, in light of Abkevich’s application to TNBC and the teaching of Telli, to utilize the method for TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli. It further would have been obvious, in light of Abkevich’s application to BRCA deficient TNBC and the teachings of Telli, to utilize the method for BRCA mutated/deficient TNBC, motivated by the desire to personalize the use of at least platinum agents and avoid unnecessary toxicity, as taught by Telli, wherein the HRD status would enable differentiation between mutations likely to be truly deleterious and those that may have unknown significance, as suggested by Telli. There would be a strong expectation of success as both are directed toward assaying the same regions and represent the application of a known technique to a known method.
The all numeric limitations identified above in the 103 rejection are noted as matters of routine optimization for the same reasons. Any additional numeric difference between the instant claims and those of the co-pending applications is likewise identified as a matter of similar/overlapping ranges and routine optimization according to the same rationales.
Any additional limitations of the co-pending claims are encompassed by the open claim language “comprising” found in the instant claims.
Response to Arguments
Applicant's arguments filed 05/05/2026 have been fully considered but they are not persuasive.
Regarding the 101 rejection, on pgs. 5-6, Applicant argues that independent claim 74 has been amended to remove “detecting” and instead recites characteristics of the sequenced DNA, and alleges, therefore, that the claims do not recite or are directed to a judicial exception. Applicant argues that the step of “sequencing DNA” is a physical process that utilizes specific machinery/devices and cannot be performed in the human mind, and alleges that the claims are directed to patent eligible methods.
In contrast to the arguments, the claims remain directed to the judicial exceptions(s) of a natural phenomenon and/or a mathematical calculation, including one that may be completed in the human mind. The claim is directed the correlation between the HR deficiency status of the TNBC cell and the number/status of LOH/TAI/LST regions in the genome of the cell. The recitation of the combined number above which the TNBC of the patient is “thereby HR deficient” also inherently requires a step of mathematically combining the numbers of LOH, TAI, and LST regions, and therefore the claim also still recites the judicial exception of a mathematical calculation. The sequencing required by the claim serves as insignificant extra-solution activity required to obtain the data necessary to assess the natural phenomenon and/or practice the mathematical calculation. Further, under Step 2B, generically recited sequencing of DNA is well-understood and routine (see MPEP 2106.05(d)(II): University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)) and therefore does not add significantly more. The remaining claims have likewise been analyzed above and have not been identified as subject matter eligible.
Regarding the 103 rejection over Abkevich, on pgs. 6-9, Applicant argues that Abkevich neither teaches nor suggests the amended independent claim 74. In particular, Applicant argues that Abkevich does not expressly disclose detecting the HR deficiency status of a BRCA deficient TNBC cell or “wherein the sequencing results comprise a combined number of ... LOH...regions, ... TAI...regions, and ... LST...regions in at least 10 pairs of human autosomes greater than or equal to 33, and wherein the TNBC cell of the patient is thereby HR deficient” as claimed.
Applicant further disagrees with the characterization of Abkevich that the threshold is taught. Applicant also argues that such would not be a matter of routine optimization, as the ability to determine a threshold of combined LOH, TAI, and LST regions for different tumor types is important. Applicant presents specification citations that contrast thresholds of > 33 and > 42, wherein Applicant recites that the > 33 threshold resulted in a larger effect size and the proportion of pCR events captured by the threshold decreased at the higher GIS threshold of > 42. Applicant also states that unexpected results provide a separate reason for patentability.
In contrast to the arguments, Abkevich does detect an HR deficiency status of a BRCA deficient TNBC cell. Fig. 16 presents a threshold of HRD scores, i.e., a “low” and a “high” HRD status and separates our patients into BRCA mutant and wild type (see also para [00346]). Para [00344] recites that these are a TNBC sample cohort.
It is also noted that Abkevich teaches restricting to autosome pairs in a method of predicting patient response comprising calculating a combined score of LOH, TAI, and LST regions and assay for polymorphic loci in at least 10 autosome pairs (para [00286]; see also para [00280]), wherein such a substituting the consideration of the whole genome (all chromosomes) to 10 or more autosomes would be a simple substitution of known element for another, wherein such would be predictable, for the motivations described in the 103, including avoid sex chromosomes to as to apply method to males, as taught by Abkevich, with a strong expectation of success given that Abkevich teaches all elements. It is also noted that such would be considered an art recognized equivalent, wherein it would have been obvious to substitute it as it was known for the same purpose, as described in MPEP 2144.06(II).
Additionally, MPEP 2131.03(I) makes clear that: "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023). Accordingly, a range of 42 or greater anticipates a range of 33 or greater, wherein the claimed range encompasses all values between 33 and the practical limits of acquisition.
Further, regarding the arguments directed to routine optimization, both Abkevich and the instant specification recite that this floor may be preferably set between 5 and 42, including preferably 30 or preferably 35 (instant para [0072-73]; Abkevich [0064-65]). As such, this does not appear to be critically set at 33, even should it be interpreted to be (or amended to recite) a particular reference value rather than a threshold indicating a range of values, which Abkevich teaches in the embodiment of the BRCA deficient TNBC samples.
While the Applicant argues that such a floor of 33 resulted in a larger effect size [within the context of response to treatment], instant para [00404] states that this occurred in the “full clinical validation cohort” and the “BRCAwt clinical validation cohort”. Instant para [00403] recites that this TNBC cohort included 211 platinum-treated samples, 171 of which were BRCA wildtype. No statistics were identified comparing the claimed BRCA TNBC subset in the discussed context. It is noted that Fig. 22A appears to characterize the cohort of the BRCA deficient TNBC tumors in the instant examples as lacking any samples with combined scores of less than about 42 (panel 2, dark grey). Thus, there is no indication that such an effect size would be present if limited to the claimed species of BRCA deficient TBCA. This is also interpreted to contribute to the differences in the probabilities of response (see Abkevich para [00100], which discusses BRCA1 mutations and synthetic lethality of platinum drugs), given that there were no BRCA deficient tumors identified below a score of about 42 in Fig. 22A, i.e., would not be interpreted to be an unexpected result.
Further, it is noted that no test statistics have been presented comparing these two odds ratios underlying the “larger effect size” and each odds ratio is within the confidence interval of other, such that is not clear if these are meaningfully different. Compounding this, a bivariable logistic regression using both thresholds as binary variables regressed against pCR is presented in para [00405], wherein it is recited that the threshold of 33 or greater fails to achieve significance. This is interpreted to indicate that the values of 33 to 41 do not significantly predict pCR, even in the full cohort.
For these reasons, it is not persuasive that there is evidence of a meaningful difference in the claimed species or that such amounts to unexpected results commensurate in scope with the claimed species. The artisan would have been expected to optimize the threshold to balance proportions
Regarding the non-statutory double patenting rejections, Applicant argues that none of the references teach “wherein the sequencing results comprise a combined number of ... LOH...regions, ...TAI...regions, and ... LST...regions in at least 10 pairs of human autosomes of greater than or equal to 33” and alleges that this is not routine optimization as previously discussed.
This is not persuasive for the reasons discussed above.
It is noted that Applicant addresses cited “Abkevich 2” (US 2014/0363521). However, as addressed in the Prior Rejections/Objections section, the clerical error in the headers was addressed in the prior office action. The citations in the double patenting rejection are those of Abkevich 2016 and references are made to the rejections of the 103 throughout. Therefore, it is determined that the Applicant has had an opportunity to respond to the rejection under Abkevich 2016.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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